The compositions of the present invention contain as pharmaceutically active ingredient caspofungin free base being a compound of formula I
which is known to be an effective antifungal and anti-protozoal agent. The aza cyclohexapeptide compound caspofungin belonging to the echinocandin family has the CAS Registry Number 162808-62-0 and the CAS Name 1-[(4R,5S)-5-[(2-Aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]-pneumocandin B0 (Merck Index online, edition 2001-2005 by Merck & Co., Inc., Whitehouse Station, N.J., USA). Caspofungin exists in a variety of pharmaceutically acceptable salts such as caspofungin diacetate as described e.g. in European Patent EP 0 904 098 B1. Caspofungin and methods for preparing it have been described e.g. in WO 94/21677 and EP 620232 which disclose inter alia caspofungin as being particularly useful in the control of mycotic infections among many other aza cyclohexapeptide compounds and their pharmaceutically acceptable salts such as hydrochloric, sulfuric, citric or other acid addition salts. Caspofungin (tris)-trifluoroacetate salt and its (tris)-hydrochloride salt have been described. WO96/24613 discloses additional processes to prepare caspofungin and in particular caspofungin diacetate salt. Caspofungin is effective in the prevention and/or treatment of infections caused by filamentous fungi and yeasts such as Aspergillus sp., Histoplasma sp., Coccidioides sp., Blastomyces sp. and/or Candida sp., as well as in preventing and/or controlling and/or treating infections such as pneumonia caused by Pneumocystis jiroveci (previously classified as Pneumocystis carinii). Caspofungin may be administered parenterally, e.g. intravenously by use of compositions being either lyophilized or liquid formulations.
European Patent EP 0 904 098 B1 or U.S. Pat. No. 5,952,300 discloses lyophilized formulations comprising caspofungin, 25 mM to 50 mM additional acetate buffer, and bulking agents such as sucrose and/or mannitol or mixtures thereof. Said formulations are stated to have enhanced chemical stability due to the use of an acetate buffer instead of a tartrate buffer. The switch to the acetate buffer is reported to result in fewer degradation products and in a more stable lyophilized formulation having an extended shelf life. The preparation of the liquid formulation which is to be lyophilized to give the final product for parenteral, in particular intravenous administration, is, however, a time consuming and fastidious procedure necessitating 2 steps of a pH-adjustment.
It has furthermore been reported that reconstitution of such lyophilized pharmaceutical compositions with a carrier solution, such as e.g. water for injection, or physiological saline, or aqueous solution of 5% glucose may lead to the formation of visible and/or sub-visible particles in the solution, as described e.g. in WO 02/41919 A1 related to pantoprazole injectable formulations. Injectable solutions such as solutions reconstituted from sterile e.g. lyophilized solids should normally be essentially free from particles that can be observed on visual inspection. For patient safety, it is also desirable that such injectable solutions have a low number of sub-visible particles. Such particles may be extraneous particles being derived e.g. from the glass of the vial containing the lyophilized product. Such sub-visible particles may e.g. result in an increased risk of embolia in a patient receiving the reconstituted product intravenously. It is known that ethylenediamine tetraacetic acid (EDTA) or its sodium salt are generally used to reduce the formation of particles in conventional pharmaceutical formulations intended for parenteral administration, e.g. lyophilized solids to be reconstituted or ready-to-use liquid formulations, such as described e.g. in WO 02/41919 A1 for pantoprazole formulations, and in U.S. Pat. No. 6,900,184 B2 for compositions containing piperacillin and tazobactam.
It would be desirable to provide a liquid or lyophilized composition comprising caspofungin which has a reduced number of sub-visible particles to increase safety for patients even without any addition of EDTA or related substances. It is furthermore desirable that such compositions have a good stability and a long shelf-life and may be manufactured by a simple and fast method.
Furthermore, an additional salt of caspofungin would be desirable to offer to the skilled person the possibility to use an alternative salt form of caspofungin. Said novel salt should be stable, should allow large scale preparation and should be easy for handling when preparing a pharmaceutical composition comprising the caspofungin salt.